NM_001673.5(ASNS):c.1393C>T (p.Arg465Ter) AND Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome - ClinVar

NM_001673.5(ASNS):c.1393C>T (p.Arg465Ter) AND Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Nov 15, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001255830.7

Allele description [Variation Report for NM_001673.5(ASNS):c.1393C>T (p.Arg465Ter)]

NM_001673.5(ASNS):c.1393C>T (p.Arg465Ter)

Genes:

CZ1P-ASNS:CZ1P-ASNS readthrough [Gene]
ASNS:asparagine synthetase (glutamine-hydrolyzing) [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.3

Genomic location:

Preferred name:

NM_001673.5(ASNS):c.1393C>T (p.Arg465Ter)

HGVS:

NC_000007.14:g.97853143G>A
NG_033870.2:g.80420C>T
NM_001178075.2:c.1330C>T
NM_001178076.2:c.1144C>T
NM_001178077.1:c.1144C>T
NM_001352496.2:c.1393C>T
NM_001673.5:c.1393C>TMANE SELECT
NM_133436.3:c.1393C>T
NM_183356.4:c.1393C>T
NP_001171546.1:p.Arg444Ter
NP_001171547.1:p.Arg382Ter
NP_001171548.1:p.Arg382Ter
NP_001339425.1:p.Arg465Ter
NP_001664.3:p.Arg465Ter
NP_597680.2:p.Arg465Ter
NP_899199.2:p.Arg465Ter
NC_000007.13:g.97482455G>A
NR_147989.1:n.3096C>T

Protein change:

R382*

Links:

dbSNP: rs373774032

NCBI 1000 Genomes Browser:

rs373774032

Molecular consequence:

NR_147989.1:n.3096C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001178075.2:c.1330C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001178076.2:c.1144C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001178077.1:c.1144C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001352496.2:c.1393C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001673.5:c.1393C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133436.3:c.1393C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_183356.4:c.1393C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome
Synonyms:: ASNS DEFICIENCY; Asparagine synthetase deficiency
Identifiers:: MONDO: MONDO:0014258; MedGen: C3809971; Orphanet: 391376; OMIM: 615574

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CEP104 [Leptonychotes weddellii]
CEP104 [Leptonychotes weddellii]
Gene ID:102747908

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001432453	Service de Génétique Moléculaire, Hôpital Robert Debré	no assertion criteria provided	Likely pathogenic	unknown	clinical testing
SCV002024374	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002766522	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 15, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001432453

Service de Génétique Moléculaire, Hôpital Robert Debré

no assertion criteria provided

Likely pathogenic

unknown

clinical testing

SCV002024374

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 12, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002766522

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 15, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Service de Génétique Moléculaire, Hôpital Robert Debré, SCV001432453.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	1	not provided

From Revvity Omics, Revvity, SCV002024374.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766522.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: ASNS c.1393C>T (p.Arg465X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant allele was found at a frequency of 1.6e-05 in 248368 control chromosomes. To our knowledge, no occurrence of c.1393C>T in individuals affected with Asparagine Synthetase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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